Monitoring tumor response with [18F]FMAU in a sarcoma-bearing mouse model after liposomal vinorelbine treatment

ObjectivePrevious studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2′-deoxy-2′-[¹⁸F]fluoro-β-d-arabinofuranosyluracil ([¹⁸F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model.MethodsFemale syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150 ± 50 mm³ (day 0), lipo-VNB (5 mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [¹⁸F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [¹⁸F]FDG/[¹⁸F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining.ResultsA significant inhibition (p < 0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [¹⁸F]FMAU-PET images of lipo-VNB-treated group declined from 2.33 ± 0.16 to 1.26 ± 0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [¹⁸F]FDG and [¹⁸F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period.ConclusionLipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [¹⁸F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB.     

A randomized, double-blind placebo-controlled trial evaluating the effects of vitamin E and selenium on arsenic-induced skin lesions in Bangladesh

OBJECTIVE: We sought to determine whether supplementation of vitamin E (alpha-tocopherol), selenium (L-selenomethionine), or their combination improves arsenical skin lesions. METHODS: A 2 x 2 randomized, placebo-controlled, double-blind trial among 121 men and women chronically exposed to arsenic in drinking water was conducted in rural Bangladesh. Participants were randomized to one of four treatment arms: vitamin E, selenium, vitamin E and selenium (combination), or placebo and were treated for 6 months. RESULTS: At baseline, the average skin lesion scores were 2.23, 2.26, and 2.63 and at follow-up, the average skin lesion scores went down to 2.00, 2.06, and 2.47 in those receiving vitamin E, selenium, and the combination, respectively. CONCLUSIONS: Supplementation with vitamin E and selenium, either alone or in combination, slightly improved skin lesion status, although the improvement was not statistically significant.     

Leiomyomatosis peritonealis disseminata--a rare case report

An infertile female aged 34 years was admitted with an abdominopelvic lump of 16 weeks size. On laparotomy innumerable nodular seedlings, in addition to uterine fibroid, simulating disseminated intra-abdominal malignancy were found. Histopathology of removed specimen of uterus and omentum revealed leiomyomatosis peritonealis disseminata.     

Carcinoma larynx--topographical distribution

One hundred and sixty subjects were included in our study, collected from four hospitals in Dhaka City. The mean age (+/- SD) of study subjects were 54.67 +/- 11.27 years. Out of 160 subjects 155 was males and 5 were females, and male to female ratio was 31:1. The highest number of study subjects was related to cultivation (40.62%). The majority of study subjects were from the low socio-economic status (68.72%). Carcinoma larynx is a multifactorial disease. Smoking and chewing habit are the most important factors associated with carcinoma larynx. Most of the male (93.12%) subjects were smoker. One hundred and fifteen (71.87%) subjects were found chewing habit of betel leaves with other ingredients. Hoarseness of voice was the commonest symptom 65.62%. Regional distribution of tumour showed supraglottic carcinoma topping the list (69.38%) followed by glottic carcinoma (30.62%) and there was no subglottic carcinoma. Site involvement in supraglottic carcinoma was found in combined location topping the list (89.20%). In glottic carcinoma majority was found glottic with supraglottic extension (65.31%). In majority cases growth were exophytic 52.50%. Palpable lymph mode was found in 48.75% of cases. All the carcinoma of larynx was found histologically of squamous cell type.     

Enhanced tumor uptake of macromolecules induced by a novel vasoactive interleukin 2 immunoconjugate

Low uptake of monoclonal antibodies (MAbs) in cancer lesions is a significant problem in cancer therapy. Recent studies have shown that antibody uptake in tumor is controlled in large part by the tumor blood flow and the vascular permeability of the tumor endothelium. We have hypothesized that these physiological properties of tumor vessels may be altered by pretreatment with vasoactive drugs or peptides linked to tumor-specific MAbs. To test this hypothesis, two MAbs, Lym-1 directed against human malignant lymphomas and B72.3 reactive with the TAG-72 antigen expressed in solid tumors, were chemically conjugated with human recombinant interleukin 2 (IL-2). IL-2 has been used in humans to activate lymphokine-activated killer cells for the treatment of cancer but is also known to produce a generalized vascular permeability by an unknown mechanism when used systemically. Chemical conjugation of IL-2 to MAbs appears to destroy its cytokine function as shown by T-cell proliferation studies in vitro. Despite this finding, MAb/IL-2 immunoconjugates retain their ability to produce an enhanced vascular permeability when injected i.v. into nude mice bearing relevant tumor models only. Biodistribution studies using 125I-labeled tracer Lym-1 have demonstrated that the Lym-1/IL-2 immunoconjugate can increase antibody uptake in tumor by a factor of 4 in a time (2.5-h pretreatment)- and dose (30 micrograms/mouse)-dependent manner. In contrast, treatment of mice with free IL-2 and antibody showed this effect in all organs of the mouse including the tumor. Bidirectional crossover imaging studies in individual tumor-bearing nude mice showed improved uptake and decreased blood pool when the MAb/IL-2 immunoconjugates were used compared to controls. Finally, tumor blood flow and vascular permeability studies demonstrate that the physiological effect of the MAb/IL-2 is due to a reversible and specific vascular leakage at the tumor site. These studies indicate that pretreatment with this novel immunoconjugate may enhance the diagnostic and therapeutic potential of MAbs, drugs, and other macromolecules for the treatment of cancer.     

Improved tumor localization and radioimaging with chemically modified monoclonal antibodies

A method for the chemical modification of monoclonal antibodies using the heterobifunctional crosslinker succinimidyl 3-(2-pyridyldithio)propionate (SPDP), has been developed which dramatically alters the physiochemical properties of antibody reagents. For these studies, three murine monoclonal antibodies, B72.3, Lym-1, and TNT-1 were used to demonstrate the effects of chemical modification on clearance and biodistribution in tumor-bearing nude mice. In vitro, all three antibodies, modified to the same degree with SPDP, showed equal immunoreactivities and lower non-specific binding. Modified antibodies also were found to have lower isoelectric points compared to unmodified controls. In vivo, modified antibodies unexpectedly were found to have 2-6 times faster clearance in tumor-bearing nude mice similar to rates obtained with their F(ab')2 fragments. Paired-label in vivo biodistribution and external imaging experiments with intact antibodies and F(ab')2 fragments demonstrated that chemically modified antibodies gave 1.5-3 fold higher tumor uptake and retained less activity in normal organs thus markedly increasing the tumor to normal organ ratios. Because of these results, chemically modified antibodies produced clearer images at earlier time points by external scintigraphy. As "stealth" molecules, chemically modified monoclonal antibodies appear to have significantly improved uptake in tumors and faster clearance times compared to native molecules. These results suggest that alteration of the physicochemical properties of monoclonal antibodies may generate improved reagents for in vivo use.     

A novel method for stereospecific fluorination at the 2′‐arabino‐position of pyrimidine nucleoside: synthesis of [18F]‐FMAU

Direct fluorination of a pyrimidine nucleoside at the 2′‐arabino‐position has been deemed to be extremely difficult, if not impossible. The conventional synthesis of 2′‐deoxy‐2′‐fluoro‐5‐methy‐1‐β‐D ‐arabinofuranosyluracil (FMAU) and its 5‐substituted analogs involves stereospecific fluorination of the 1,3,5‐tri‐O‐benzoyl‐α‐D ‐ribofuranose‐2‐sulfonate ester followed by bromination at the C₁‐postion, and then coupling with pyrimidine‐bis‐trimethylsilyl ether. Several radiolabeled nucleoside analogs, including [¹⁸F]FMAU, and other 5‐substituted analogs, were developed according to this methodology. However, routine production of these compounds using this multi‐step process is inconvenient and limits their clinical application. We developed a novel precursor and method for direct fluorination of preformed nucleoside analogs at the 2′‐arabino position, exemplified via radiosynthesis of [¹⁸F]FMAU. The 2′‐methylsulfonyl‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐ribofuranosiluracil was synthesized in multiple steps. Radiofluorination of this precursor with K¹⁸F/kryptofix produced 2′‐deoxy‐2′‐[¹⁸F]fluoro‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐arabinofuranosiluracil. Acid hydrolysis followed by high‐performance liquid chromatography purification produced the desired [¹⁸F]FMAU. The average radiochemical yield was 2.0% (decay corrected, n=6), from the end of bombardment. Radiochemical purity was >99%, and specific activity was >1800 mCi/µmol. Synthesis time was 95–100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of [¹⁸F]FMAU, and the method should be suitable for production of other 5‐substituted pyrimidine analogs, including [¹⁸F]FEAU, [¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, and [¹⁸F]FBAU. Copyright © 2010 John Wiley & Sons, Ltd.     

Utilization of second derivative photoplethysmographic features for myocardial infarction classification

Myocardial infarction (MI) is a common disease that causes morbidity and mortality. The current tools for diagnosing this disease are improving, but still have some limitations. This study utilised the second derivative of photoplethysmography (SDPPG) features to distinguish MI patients from healthy control subjects. The features include amplitude-derived SDPPG features (pulse height, ratio, jerk) and interval-derived SDPPG features (intervals and relative crest time (RCT)). We evaluated 32?MI patients at Pusat Perubatan Universiti Kebangsaan Malaysia and 32 control subjects (all ages 37–87?years). Statistical analysis revealed that the mean amplitude-derived SDPPG features were higher in MI patients than in control subjects. In contrast, the mean interval-derived SDPPG features were lower in MI patients than in the controls. The classifier model of binary logistic regression (Model 7), showed that the combination of SDPPG features that include the pulse height (d-wave), the intervals of “ab”, “ad”, “bc”, “bd”, and “be”, and the RCT of “ad/aa” could be used to classify MI patients with 90.6% accuracy, 93.9% sensitivity and 87.5% specificity at a cut-off value of 0.5 compared with the single features model.     

Analysis of myocardial infarction signals using optical technique

The risk of heart attack or myocardial infarction (MI) may lead to serious consequences in mortality and morbidity. Current MI management in the triage includes non-invasive heart monitoring using an electrocardiogram (ECG) and the cardic biomarker test. This study is designed to explore the potential of photoplethysmography (PPG) as a simple non-invasive device as an alternative method to screen the MI subjects. This study emphasises the usage of second derivative photoplethysmography (SDPPG) intervals as the extracted features to classify the MI subjects. The statistical analysis shows the potential of “a-c” interval and the corrected “a-cC” interval to classify the subject. The sensitivity of the predicted model using “a-c” and “a-cC” is 90.6% and 81.2% and the specificity is 87.5% and 84.4%, respectively.